Acquired drug resistance (DR) largely limits the effectiveness of targeted cancer therapies, especially for aggressive diseases, such as mantle cell lymphoma (MCL), a B-cell lymphoma with poor prognosis. Recently, FDA approved drug Venetoclax (ABT-199), a novel, potent and selective small-molecule BCL-2 inhibitor was clinically vetted as an effective therapy for hematopoietic tumors, including MCL. The use of ABT-199 produced a dramatic response; however, the emergence of resistance to this drug was ensued by fatal progression of the MCL. Once MCL patients relapse from ABT-199 treatment, either during or after, there is rapid disease progression and accelerated mortality. Thus, there is an urgent need to define mechanisms of ABT-199 resistance (AR) and identify targets to bring forward novel treatment options with tangible curative potential. We modeled drug resistance to ABT-199 by generating AR cell lines from MCL, and characterized the adaptive molecular reprogramming to ABT-199 treatment in these cells. Small subpopulations of lymphoma cells were consistently detected that evade strong selective ABT-199 pressure by entering a reversible drug tolerant 'persister' state (DTP), and consequently leading to a DTP expansion population (DTEP) and eventual acquisition of bona fide drug resistance. Given the premise that a myriad of mechanisms are involved in MCL AR, we applied network-wide, robust and unbiased approaches to determine the major altered MCL signaling pathways during AR evolution. More complex and more dynamic than we had anticipated, we observed that these DTEP cells conferred increased viability and clonogenic growth, associated with BH3 family protein reprogramming. Intriguingly, DTEP cells can revert back to drug sensitive states after long-term passaging without the drug, supporting the notion that these cells are epigenetically reprogrammed to drug resistant states. Consistent with these results, our initial drug screen revealed the exquisite sensitivity to epigenetic machinery inhibitors (e.g., BRD4, CDK7) in ABT-199 DTEP cells when compared with parental cells. In line with this, our immunoprecipitation-sequencing (ChIP-Seq) and RNA-Seq assays revealed dynamic super enhancer (SE) remodeling in DTEP MCL cells, and this chromatin alteration is associated with CDK7-mediated transcription in ABT-199 resistant MCL cells. We propose that transcriptional and epigenetic adaptive responses are required for the survival of cells that persist in the presence of ABT-199 therapy. The objective of this proposal is to strategically target transcriptional machinery and provide pre-clinical validation by targeting CDK7/BRD4, in combination with BCL-2 as an efficient and durable treatment for MCL. With the small molecule tools for epigenetic targets and patient-derived xenograft (PDX) model available in the Qi and Tao laboratories, respective expertise and the unique access to a large resource of primary MCL samples, the study allows us to gain valuable insights into MCL drug resistance biology and uncover a novel mechanism- driven therapy for MCL patients.